Inhibition of Wnt/β‐Catenin Signaling Promotes Engraftment of Mesenchymal Stem Cells to Repair Lung Injury

Abstract

We sought to explore the treatment effects and the repair mechanisms of bone marrow derived mesenchymal stem cells (MSCs) during HCl-induced acute lung injury (ALI). MSCs were delivered through the tail veins of rats 24 h after intranasal instillation of HCl. The results showed that MSCs did not ameliorate the histopathologic changes of ALI and pulmonary fibrosis. We found that the activated Wnt/β-catenin signaling may regulate the differentiation of MSCs and is associated with lung fibroblasts activation, pulmonary fibrosis and tissue repair process in ALI rats. Immunofluorescence and histology analysis indicated that activated canonical Wnt/β-catenin signaling induced most MSCs to differentiate into myofibroblasts or fibroblasts in vivo. However, inhibition of Wnt/β-catenin signaling by Dickkopf-1 (DKK1) promotes epithelial differentiation of MSCs induced by native alveolar epithelial cells which are beneficial to repair the injured lung epithelium. Inhibition of Wnt/β-catenin signaling after MSCs transplantation ameliorated pulmonary fibrosis and improved pulmonary function which attenuated the lung injury. In vitro study, activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblasts markers, which was attenuated by DKK1. Furthermore, Wnt3α activated Wnt/β-catenin signaling in lung fibroblasts to enhance the expression of collagen I, vimentin and α-smooth muscle actin, but DKK1 attenuated these proteins expression. These findings demonstrated that canonical Wnt/β-catenin signaling plays a key role in regulating differentiation of MSCs in vivo or in vitro and the pathogenesis of fibrotic diseases. Our study suggested that inhibition of abnormal activated Wnt/β-catenin signaling would promote MSCs epithelial differentiation to repair lung injury and reduce pulmonary fibrosis.

A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin

“…Upon stimulation by Wnt ligands, b-catenin is stabilized and then translocates to the nucleus, where it binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, activating the expression of Wnt target genes, promoting cell proliferation (15)(16)(17) and limiting cell differentiation (16,18), thus contributing to both airway (18,19) and alveolar epithelial repair (20)(21)(22) after injury. Consistent with this concept, activation of b-catenin signaling by lithium chloride attenuated elastase-induced experimental emphysema (21), suggesting that b-catenin signaling contributes to lung repair/regeneration in response to various injuries.…”

Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury

“…XAV939 could significantly suppress Wnt/␤-catenin signaling and promote the epithelial differentiation but had little impact on ATII cells. Previous reports suggested that when the Wnt/ ␤-catenin signaling is activated, BM-MSCs can differentiate into fibroblasts or myofibroblasts, and this process can be inhibited by DKK-1 (34). These findings prompted us to propose that inhibition of Wnt/␤-catenin signaling could promote the alveolar epithelial cell-mediated differentiation of autologous BM-MSCs into epithelial cells in the damaged lung, and hence the improvement in lung function.…”

“…Mesenchymal stem cells did not abrogate the histopathologic changes of HCl-induced acute lung injury and pulmonary fibrosis. We have previously shown that inhibition of Wnt/␤-catenin signaling by DKK-1, a natural inhibitor of the Wnt/␤-catenin signaling pathway, can promote the differentiation of exogenous BM-MSCs into epithelial cells in vivo and thus regulate lung injury and repair, although only a fraction of the exogenous cells are recruited (34). In addition, recruitment of endogenous mesenchymal stem cells to the injured lung is also observed (40).…”

A two-pronged weapon in the fight against fibrosis. Focus on “Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury”

“…The study by Wang and coworkers, along with prior publications from this group and others (6,11,13), makes clear that the Wnt/␤-catenin signaling pathway plays a major role in pulmonary fibrosis. This pathway appears to affect two key cell types involved in lung injury and repair: it activates fibroblast proliferation and inhibits mesenchymal stem cell differentiation into epithelia (instead promoting differentiation into a fibroblast-like phenotype).…”